1、汐萀q9拴溨q9拵烁萀q9拶鳁q9拷萀q9拸q9拹萀q9拺磁q9拻萀q9拼尀q9拽品萀q9拾胁尀q9拿萀q9棖惁q9棗賁萀q9棘q9棙萀q9棚q9棛铁萀q9棜q9棝萀q9棞q9棟烁萀q9棠鳁q9棡q9棢q9棣磁q9缷q9缸郁q9缹簀q9缺峁q9缻簀q9缼q9缽簀q9缾郁q9缿贐簀q9罀鋬q9罁飈況簀q9罂鱌q9罃簀q9罄q9罅簀q9罆q9罇簀q9罈僁q9罉簀q9罊q9罋簀q9罌蓁q9罍q9罎q9罏q9罐賁q9网q9罒q9罓棁q9罔q9罕q9罖q9罗飁q9罘尀q9罙q9罚瓁尀q9罛q9罜尀q9罝僁q9罞檌尀Letter of access ASMF/EDMF递交 EDMF只能在MAA的支持下递交
2、 EDMF的持有者递交到 MAMA的持有者的持有者: AP的最近版本的复印件 QOS的复印件 EDMF持有者应当把AP包含的非保密内容的准阅信递交到到官方部门官方部门 有封面信的完整EDMF 准阅信 ARED E. TIEFENBACHER (GmbH e.g Benzene in Toluol Starting material : justification, characterisation, specification , including potential impurities Discussion of possible carrying through of impuriti
3、es Analytical test methods description In case the synthesis of API consits of only one or a few steps , manufacture of the staring material should be given If more than one supplier of the starting material is used, batch analysis results from the API manufactured from the different suppliers to be
4、 given 3.2.S.2.3 物料控制 原料和溶剂的规格，适当的 如果在溶剂中可能有一类溶剂应注明其规格和检测方法；如：甲苯中的苯 起始物料: 评定，性状，规格，包括潜在杂质 讨论运行中可能的杂质 分析检测方法的描述 如果原料药的合成仅有一步或几步构成，起始物料的制造应详细描述 如果所使用的起始物料的供应商不只一个，从不同的供应商生产而来的原 料药的批分析结果应被提供。 3.2.S 2.4 Control of Critical steps and intermediates : Critical steps definition: where process conditions , t
5、est requirements or other relevant parameters must be controlled within the predetermined limits to ensure that AS meets specification Description of In Process controls Intermediates : Information on the quality and control of intermediates 3.2.S 2.4 关键步骤和中间体的控制： 关键步骤的定义：工艺条件，检测要求或其他相关参数必须控制在预先确定 的
6、限度内的以确保AS符合标准 过程控制的定义 中间体 : 质量信息和中间体的控制 3.2.S.2.5 Process validation and/or evaluation Process Validation should be provided as appropriate: Sterilisation process, including filtration and aseptic processing In case the monograph indicates specific additional requirements compliance should be demons
7、traeted For biological substances , specific microbial grade, suitable inactivation should be demonstrated 3.2.S 2.6 Manufacturing process development Description and discussion 3.2.S.2.5 工艺验证和/或评估 应提供适当的工艺验证： 消毒工艺，包括过滤和无菌工艺 如果药典专论中指出专门附加的要求，准则应该被证明 对于生物物质，专门的微生物指标，适当的失活应当被证明 3.2.S 2.6 制造工艺开发 描述和讨论
8、3.2.S.3 Characterisation 3.2.S 3.1 Elucidication of Structure and other Characteristics : Evidence of chemical structure : Elemental analysis, IR spectra, NMR, MS, UV spectra Evidence of structure of key intermediates, X-Ray christallography, optical rotation Physico-chemical Characteristics : Polym
9、orphism, Melting point, DSC Solubility pKa and pH values 3.2.S.3 性状 3.2.S 3.1 结构分析和其他性状： 化学结构的证据： 元素分析，红外光谱，核磁共振，质谱，紫外光谱 关键中间体的结构证据，X-射线晶型图，旋光度 物理化学特性 : 多态性，熔点，DSC 溶解度 pKa 和 pH 值 3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Requirements concerning related substances according to the general monog
10、raph Substances for Pharmaceutical Use (2034) and the Guideline Control of impurities of pharmacopoeial substances ( QWP 1529/04) should be met Possible impurities considered as potential impurities arising from the synthesis should be discussed , indicating origin ( staring material, reagent, solve
11、nt,catalyst, intermediate or degradation product Discussion of possible routes of degradation Analytical methods ( LOD and LOQ) 3.2.S.3 性状 3.2.S 3.2 杂质 : 关于相关物质的要求，根据总的专论药品使用的物质（2034） 应符合 药品物质的杂质控制指南 ( QWP 1529/04) 应该对可能的杂质进行讨论，对认为是在合成中出现的潜在杂质，指出杂质起 源（起始物料，试剂，溶剂，催化剂，中间体或降解产物 讨论降解可能的路线 分析方法 ( LOD 和 L
12、OQ) 3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Suitability of the methods of the monograph to control the quality of the substance must be discussed and demonstrated Additional impurities above the reporting threshold demonstrating that Ph. Eur Method is suitable If Ph. Eur, method not suitable
13、 alternative test method including validation is required Chromatograms for production batches, with peak area results Additional related substances , identification and qualification accord. to the Guidance Imp. In new Drug Substances ( ICH/2737/99) 3.2.S.3 性状 3.2.S 3.2 杂质: 必须讨论和证明药典规定的原料药质量控制方法的适应
14、性 添加的杂质在报告的阈值之上，以此证明欧洲药典的方法是合适的 如果欧洲药典的方法不适应，则需要替代的检测方法，并包括其相关的验证。 生产批次有峰面积结果的图谱 附加的相关物质，鉴别和验证符合在新原料药中的杂质的指南 ( ICH/2737/99) 3.2.S.3 Characterisation 3.2.S 3.2 Impurities : Other impurities : residuals of toxic reagents, residues of acids or bases should be discussed Consider relevant guidelines Resi
15、dual catalysts , possible carryover, justified control limits required 3.2.S.3 性状 3.2.S 3.2 杂质 : 其它杂质：有毒试剂的残留，酸或碱的残留应被讨论 考虑相关的指南 催化剂残留，可能的运行产物，所要求的合理的控制限度 3.2.S.4 Control of the Active substance 3.2.S 4.1 Specification : Description Identification Impurities Assay Additional tests Reference to : Imp
16、urities testing guideline ( ICH/2737/99) Note for Guidance on Specifications ( ICH /367/96) In case monograph under revision , new draft will be taken into consideration 3.2.S.4 活性物质的控制 3.2.S 4.1 规格： 描述 鉴别 杂质 含量 附加的检测 参考：杂质检测指南 ( ICH/2737/99) 关于规格的指南的注解( ICH /367/96) 如果专论在审核中，可以考虑新的草案 Specification
17、of the Active Substance ICH/367/96 Note for Guidance on Specifications: Guidance for setting acceptance criteria Justification of specifications Selection of test procedures , pharmacopoeial tests ICH/2737/99 Impurities testing guideline Classification of impurities; residual solvents, starting mate
18、rial, intermediates, by-products, degradation products Reporting impurities, quantitative results numerical terms ! Reporting threshold, identification threshold, qualification threshold NMT 2g/day Ident. 0.1 %, Qualif. 0.15 % MT 2g/day Ident. 0.05 %, Qualif. 0.05 % 活性物质的规格 ICH/367/96规格指南的注释 ： 建立可接受
19、的标准的指南 规格的说明 检测规程，药典检测方法的选择 ICH/2737/99 杂质检测指南 杂质的分类；残留溶剂，起始物料，中间体，副产物，降解产物 报告杂质，以数据定量的结果！ 报告阈值，鉴别阈值，验证阈值 NMT 2g/天， 鉴别的 0.1 %, 数量 0.15 % MT 2g/天，鉴别的 0.05 %,数量 0.05 % 3.2.S.4 Control of the Active substance 3.2.S 4.2 Analytical Proecedures Details of the analytical procedures In case of TLC methods i
20、n the monograph , suitability to detect imp. at relevant threshold ( 0.05% or 0.03 % acc. Max. daily dose) TLC method only accepted in rare cases , Requirements of suitability , detection and quantification limit have to be considered 3.2.S.4 活性物质的控制 3.2.S 4.2 分析规程 分析规程的详细内容 如果是在专论中的TLC方法，在相关阈值内杂质检测
21、的适应性( 0.05% 或 0.03 % 根据日常最大计量) 仅在很少的情况下，可接受TLC方法 应考虑适应性，检测限和定量限的要求 3.2.S.4 Control of the Active substance 3.2.S 4.3 Validation of Analytical Procedures Reference to validation of analytical methods (ICH 381/95 and ICH 281/95); Typical chromatograms For additional methods acc. To the general methods
22、 of the Ph. Eur, like for residual solvents applicability is sufficient 3.2.S.4 活性物质的控制 3.2.S 4.3 分析规程的验证 分析方法验证的参考 (ICH 381/95 和ICH 281/95); 典型的图谱 对于附加的方法，根据欧洲药典的一般方法，象残留溶剂，适应性就足够了 3.2.S.4 Control of the Active substance 3.2.S 4.4 Batch Analysis Description of batches and results of batches Results
23、 below 1 % for related substances should be reported with 2 digits Present actual figures whenever possible instead of only complies Analytical results from min. 2 batches, maximum batch size Results should include : Date of manufacture, batch size and batch number, place of manufacture, results of
24、analytical test, use of batches 3.2.S.4 活性物质的控制 3.2.S 4.4 批分析 批次描述和批次结果 结果小于1的相关物质应用2位数报告 现在的实际数据，每当可能时只是代替“遵守” 分析结果从最少2批到最大批数量 结果应当包括: 制造日期, 批大小和批号, 制造地点, 分析检测结果, 批的使用 3.2.S.4 Control of the Active substance 3.2.S 4.5 Justification of Specification See Note for Guidance on Specification, impurity t
25、esting guideline, residual solvents 3.2.S 5 Reference Standards or Materials Specifications, full analytical and physico-chemical charcterisation, impurities etc. Reference substances ( primary and secondary) incl. full analytical results or Ph. Eur. CRS 3.2.S 6 Container Closure System Description
26、of bulk storage container closure Specification of primary packaging material ( e.g. Poleythylene bags) ad secondary packaging ( e.g. fibre drums, metal drums) 3.2.S.4 活性物质的控制 3.2.S 4.5 规格的解释 查看指南中有关规格，杂质检测指南，残留溶剂的注解 3.2.S 5 对照品或对照物 规格，完整的分析和物理化学特性，杂质等 对照品（基准和二级）包括完整的分析结果或EP标准品 3.2.S 6 容器密闭系统 存放物料的密
27、闭容器的说明 第一层包装材料（例如聚乙烯袋）和第二层包装（例如纤维桶，金属桶）的规 格 3.2.S 7 Stability 3.2.S 7.2 Post approval stability Protocol and commitment Retest period may be attributed based on extrapolation , see NfG on stability testing 3.2.S 7.3 Stability Data Detailed results in tabular format, Stability testing according to IC
28、H guideline information on the analytical procedures ( validation if necessary ) 3.2.S 7 稳定性 3.2.S 7.2 公布批准的稳定性方案和执行 复测周期可以基于外推法来定性，参见NfG 稳定性试验 3.2.S 7.3 稳定性数据 以表格形式的详细结果 根据ICH指南进行稳定性试验 基于分析规程（如果必要须验证）的信息 References Notice to applicants (NTA) Volume 2 B CTD Module 3 S Guideline on the chemistry of n
29、ew active substances Validation of analytical methods , Analytical procedures methodology ICH Stability testing, photostability testing ICH Impurities testing guideline , residual solvents ICH. Note for Guidance on Specifications 参考文献 通知申请者 (NTA) 第2册 B CTD 模块 3 S 新活性物质化学部分指南 ICH 分析方法验证, 分析规程方法学 ICH
30、稳定性试验, 光稳定性试验 ICH 杂质试验指南，残留溶剂 指南中关于规格的注意 ALFRED E. TIEFENBACHER (GmbH defined chemical properties and structure! 1. 介绍 1.2 药政适应性 当一种物料被一个地区或国家列为原料药，在该地 区制造或在某种药物产品中使用，必须根据本指南 遵循GMP要求。 1.3 范围 本指南应用于由化学合成，提取，细胞培养/发酵， 自然原料提取的原料药制造。 原料药起始物料是原料，中间体，或一种原料药， 它具有所要生产的原料药的有效结构部分；明确的 化学属性和结构 Application of th
31、e Guide to API Manufacturing Chemical synthesis: production of API starting material- introduction of API starting material into process production of intermediate(s) isolation and purification- physical processing and packaging Derived from animal sources: collection of organ, fluid, or tissue cutt
32、ing, mixing, initial processing introduction of the API starting material into process isolation. Extracted from plant sources: collection of plants cutting and initial extraction further extraction physical processing API consisting of comminuted or powdered herbs: collection cutting/comminuting ph
33、ysical processing and packaging Biotechnology-Fermentation/cell culture: establishment of master and working cell bank maintenance of working cell bank cell culture/fermentation isolation and purification physical processing and packaging Classical“ fermentation to produce an API: Establishment and
34、maintenance of the cell bank introduction of the cells into fermentation,. 本指南在原料药制造的运用 化学合成：原料药起始物料的生产在工艺中加入原料药起 始物料中间体生产分离和提纯物理加工和包装 源于动物原料的：采集器官，液体，或组织切割，混和， 初步加工在工艺中加入原料药起始物料分离 从植物原料中提取的：采集植物切割和初步提取进一步 提取物理加工 原料药由粉末或粉末状草药组成：采集切割/粉末化物理 加工和包装 生物技术发酵/细胞培养：建立主细胞库和工作细胞库工 作细胞库的维护细胞培养/发酵分离和提纯物理加工和 包装 生
35、产一个原料药标准的发酵：细胞库的建立和维护在发酵 中加入细胞 1.3 Scope The company should designate and document the rationale for the point at which proiduction of the API begins. (available?, inspectors aide memoire!(AM) From this point on ,appropriate GMP as defined in the Guide should be applied to these intermediate and/or API manufacturing steps. This includes validation of critical process steps determined to impact the quality of the API.(AM critical steps identified?) The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to f
